Systemic lupus erythematosus (SLE) affects 1.5 million Americans and 5 million people worldwide. Therapies for SLE are ineffective and slow to emerge due in large part to lack of mechanistic understanding of the disease. The long-term goal of this research is to elucidate cellular and molecular mechanisms of SLE with the objective of identifying viable therapeutic targets. Recent studies demonstrate that SLE patients have quantifiable changes in circulating microRNAs (miRNAs). miRNAs are small non-coding RNAs with high gene regulatory potential and function in cell-to-cell communication. We recently reported that high density lipoprotein (HDL) transfers functional miRNAs to cells in a scavenger receptor BI (SR-BI)-dependent manner. Interestingly, studies show that SLE patients have HDL that is not only deficient in regulating cholesterol homeostasis, but lacks many anti-inflammatory properties. We hypothesize that changes in HDL-miRNAs and dysregulation of HDL-mediated miRNA transfer between immune cells is an important molecular mechanism in SLE pathogenesis. We present preliminary data demonstrating that HDL-miRNAs in SLE patients are altered compared to healthy controls and that these alterations are recapitulated in an animal model of SLE, the congenic B6.SLE1.2.3 mouse. In addition, we demonstrate that T and B cells take up HDL cholesterol and associated miRNAs. Using this mouse strain, we will determine that, in SLE, altered HDL-miRNAs serve as a mechanism for T and B cell dysregulation contributing to disease pathogenesis. We propose two specific aims. The first will determine effects of altered HDL-miRNAs on T cell homeostasis, gene expression and B cell cooperation. The second will explore therapeutic potential for targeting HDL-miRNAs in SLE. These aims will be executed using established and novel methods, including high-throughput small and long RNA sequencing, PhotoActivatable Ribonucleoside CrossLinking ImmunoPrecipitation (PAR-CLIP), and high-end bioinformatics. Successful completion of these studies will lead to advances in our current understanding of molecular mechanisms of SLE and will identify HDL-miRNAs as therapeutic targets for a disease for which treatment options have been lacking.